Effect of erythropoietin on lipid profile in haemodialysis patients

Summary: Effect of recombinant human erythropoietin (rHuEPO) was determined on lipid levels (i.e. total cholesterol, triglycerides, high density lipoproteins [HDL], low density lipoproteins [LDL]) of 17 anaemic patients on maintenance haemodialysis. Estimations were done before initiating rHuEPO therapy and repeated 6 months later. There was an increase in haemoglobin (7.6 ± 1.09 to 10.9 ± 1.62 gm/dL, P < 0.001), and a significant decrease in total cholesterol (217 ± 22 to 196 ± 18 mg/dL, P < 0.001) and triglyceride levels (200 ± 20 to 186 ± 15 mg/dL, P < 0.001). There was no significant effect on HDL and LDL levels.     

The impact of withdrawing ACE inhibitors on erythropoietin responsiveness and left ventricular hypertrophy in haemodialysis patients.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have the capability of decreasing left ventricular mass index (LVMI) in chronic haemodialysis (HD) patients. On the other hand, recent reports provide conflicting information regarding the impact of ACE inhibitors on responsiveness to recombinant human erythropoietin (rHuEpo), and there are no data about the effect of withdrawing ACE inhibitors both on rHuEpo response and LVMI in HD patients. METHODS: ACE inhibitors were switched to another antihypertensive medication in 23 out of 68 patients in our HD unit who were receiving both rHuEpo and an ACE inhibitor for more than 1 year. Blood pressure at the pre- and post-dialysis phases, haematocrit levels and rHuEpo doses were determined at the end of the first and of the third years, and the LVMI was determined at the end of the third year. Statistical analyses were done in 15 patients in whom the study could be completed. RESULTS: The mean (+/-SD) haematocrit level was increased from 26.3+6.4% to 29.8+/-6.3% at the first year (P<0.05), and to 29.4+/-6.5% at the third year (P<0.05 vs before), while the mean dose of rHuEpo was decreased from 208.3+/-99.0 UI/kg/week to 141.0+/-91.8 at the first year (P=0.01), and to 141.4+/-81.0 at the third year (P=0.01 vs before). Administration of rHuEpo had been stopped in two patients at the end of the first year. The mean blood pressure level and the mean LVMI were not changed (P>0.05 vs before). There were no significant changes in dialysis parameters, iron status, plasma renin activities, and levels of aldosterone, intact parathyroid hormone, aluminum and erythropoietin. CONCLUSION: The findings of this small uncontrolled study indicate that withdrawal of ACE inhibitors in hypertensive chronic HD patients receiving rHuEpo may result in an increase in haematocrit level, and a decrease in dose of rHuEpo without any significant changes in the blood pressure level and LVMI. Controlled prospective studies are needed to clarify this issue.     

Regular low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients

BACKGROUND.: Erythropoietin (Epo) is an effective but expensive treatmentfor anaemia in patients with chronic renal failure. Hyporesponsivenessto Epo, particularly in haemodialysis patients, is most commonlydue to a functional iron deficiency, which is difficult to monitorreliably. METHODS.: Forty-six stable haemodialysis patients, receiving Epo therapy,were commenced on regular low-dose intravenous iron (sodiumferric gluconate complex) at a dose of 62.5 mg/5 ml given asa slow injection post-dialysis twice weekly, weekly, or fort-nightly,according to their serum ferritin levels. Haemoglobin, serumferritin, Epo dose, and iron dose were measured at 6-weeklyintervals over a 6-month period. RESULTS: At the beginning of the study, 12 patients in the group hadferritin levels of less than 100 µg/l, and were thus consideredto potentially have an absolute iron deficiency. The study groupwas therefore split into two subgroups for the purpose of analysis,i.e. the 12 patients with ferritin levels of less than 100 µg/lat the start of the study or ‘low ferritin group’,and the remaining 34 patients with ferritin levels of greaterthan 100 µg/l at the start of the study or ‘normalferritin group’. In the low ferritin group (n=12), intravenous iron therapy increasedserum ferritin levels, and produced a significant rise in haemoglobin,and a significant reduction in Epo dose. (Ferritin pre-iron,median (range) 68 (20–96)µg/l; post-iron, 210.5(91–447)µg/l, P<0.003, Wilcoxon. Haemoglobinpre-iron, 10.05 (8.2–11.9)g/dl; post-iron, 11.0 (9.9–11.9)g/dl,P<0.03. Epo dose pre-iron, 9000 (4000–30000) i.u./week;post-iron, 6000 (2000–10000)i.u./week, P<0.05.) Similar results were obtained in the normal ferritin group (n=34)following intravenous iron therapy, with significant increasesin serum ferntin levels and haemoglobin concentrations, anda significant reduction in Epo dose. (Ferritin pre-iron, 176(103–519) µg/l; post-iron, 304.5 (121–792)µg/l,P<0.0001. Haemoglobin pre-iron, 9.85 (6.5–12.8)g/dl;post-iron: 11.25 (9.9–13.3)g/dl, P<0.0001. Epo dosepre-iron, 6000 (2000–15 000)i.u./week; post-iron, 4000(0–15000)i.u./week, P<0.005.) CONCLUSION.: Regular intravenous iron supplementation in haemodialysis patientsimproves the response to Epo therapy.     

Does erythropoietin cause hormonal changes in haemodialysis patients?

In 10 female and 10 male haemodialysis patients plasma FSH,LH, testosterone, prolactin, and somatotropin (STH) were estimatedduring erythropoietin (rHuEpo) treatment for 6 months. All butone patient responded with an increase in haemoglobin. The patientsexperienced improved sexual function according to the answersgiven in a self-administered questionnaire. Of the 90% who answeredbefore the study 22% could not perform sexual activities whetherthey wanted to or not. During and at the end of the study 80and 60% respectively answered, and none had these problems.In contrast, serum values of the sexual hormones (FSH, LH, testosteroneand prolactin) were not significantly changed during rHuEpotherapy, and neither was the basal plasma STH.     

Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin

SUMMARY: We assessed the efficacy of intravenous (i.v.) iron saccharate (VENOFER) vs oral iron supplementation in haemodialysis patients treated with low-dose erythropoietin (EPO). Twenty haemodialysis patients with serum ferritin >200 ng/mL and transferrin saturation >30% were assigned to one of the two groups. In Group 1, 10 were given i.v. iron saccharate (100 mg i.v. twice weekly) post dialysis. In Group 2, oral ferrous sulphate 200 mg was given thrice daily. In both groups, subcutaneous EPO 25 units/kg body weight (BW) was started simultaneously, twice weekly. After 3 months (study completion) the mean haemoglobin and haematocrit was significantly increased in Group 1 than in Group 2 (Hb 11.60 ± 0.64 G/ dL vs 10.5 G/dL ± 1.14 P <0.01). the final mean EPO dose was 25% lower in Group 1 than in Group 2 (3400 ± 1356 U/week vs 4600 ± 1356 U/week P =0.10) and the mean serum ferritin was higher in the i.v. iron group than the oral group (671 ng/mL ± 388 vs 367 ng/mL ± 238 P =NS). the same was also observed with transferrin saturation (44.6%± 19.8 in Group 1 vs. 29%± 11.0 in Group 2 P =NS). No adverse effects were seen during the study. In conclusion, we observed that regular use of i.v. iron had a significantly enhanced haemoglobin response, better maintained serum ferritin and lower EPO dosage requirement than the oral iron group.     

Crossover comparison of intravenous and subcutaneous erythropoietin in haemodialysis patients.

To examine the suggestion that s.c. administration of recombinant human erythropoietin (rHuEpo) may be more effective than i.v. administration, we changed the route of administration in 11 patients, previously established on a stable dose of rHuEpo given twice or thrice weekly, from i.v. to s.c. administration without altering the dose. All patients were iron replete (serum ferritin greater than 100 micrograms/l). In one patient the haemoglobin concentration declined at the time of conversion due to poor compliance, and another patient died shortly after conversion. In the remainder there was a significant increase in haemoglobin concentration from 9.30 (SD 0.78) at the time of conversion to 9.84 (0.59) at 1 month, 10.35 (1.22) at 2 months, and 10.39 (1.42) at 3 months. The increase in haemoglobin concentration was greater than 1 g/dl at 3 months in only five of the patients. Serum ferritin prior to conversion was similar in 'responders' and 'non-responders', but all responders had a transferrin saturation of greater than 16%, whereas three of four non-responders had transferrin saturation of less than or equal to 16%. Subcutaneous administration of rHuEpo is more effective, dose for dose, than i.v. administration, but poor iron mobilization may limit the response.     

Aluminium overload and response to recombinant human erythropoietin in patients under chronic haemodialysis.

In this work, of 51 patients treated by rHuEpo, 25 were selected for study. The selection criteria were absence of clinically evident causes of anaemia other than end-stage renal failure, such as chronic infection, active systemic disease, bleeding sites, and vitamin B12 or iron deficiencies. Serum aluminum was assessed before dialysis and the presence of aluminium overload was confirmed by a DFO test. rHuEpo was given in a dose of 50 U/kg body-weight after each dialysis session three times weekly and the response to treatment was evaluated monthly for 8 months. Our data showed significant correlation between serum aluminum and the response to rHuEpo. The response was significantly greater in those with lower serum aluminium. We conclude that the aluminium load in chronic haemodialysis patients may have an effect on the response to rHuEpo.     

Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin

We assessed the efficacy of intravenous (i.v.) iron saccharate (VENOFER) vs oral iron supplementation in haemodialysis patients treated with low-dose erythropoietin (EPO). Twenty haemodialysis patients with serum ferritin >200 ng/mL and transferrin saturation >30% were assigned to one of the two groups. In Group 1, 10 were given i.v. iron saccharate (100 mg i.v. twice weekly) post dialysis. In Group 2, oral ferrous sulphate 200 mg was given thrice daily. In both groups, subcutaneous EPO 25 units/kg body weight (BW) was started simultaneously, twice weekly. After 3 months (study completion) the mean haemoglobin and haematocrit was significantly increased in Group 1 than in Group 2 (Hb 11.60±0.64 G/dL vs 10.5 G/dL±1.14 P <0.01). The final mean EPO dose was 25% lower in Group 1 than in Group 2 (3400±1356 U/week vs 4600±1356 U/week P =0.10) and the mean serum ferritin was higher in the i.v. iron group than the oral group (671 ng/mL±388 vs 367 ng/mL±238 P =NS). The same was also observed with transferrin saturation (44.6%±19.8 in Group 1 vs. 29%±11.0 in Group 2 P =NS). No adverse effects were seen during the study. In conclusion, we observed that regular use of i.v. iron had a significantly enhanced haemoglobin response, better maintained serum ferritin and lower EPO dosage requirement than the oral iron group.     

Long-term therapy with recombinant human erythropoietin increases CD8+ T-cell apoptosis in haemodialysis patients.

BACKGROUND: We intended to assess the intensity of apoptosis in the CD4+ and CD8+ T-lymphocytes of haemodialysis (HD) patients on recombinant human erythropoietin (rHuEpo). METHODS: The expression of Fas, tumour necrosis factor-alpha receptors (TNFRI and TNFRII) and the CD28 molecule on lymphocytes was evaluated in 15 HD patients before and during treatment with rHuEpo. In cultures of peripheral blood mononuclear cells (PBMCs) stimulated with rHuEpo, phytohaemagglutinin and camptothecin, our measures of apoptosis were the percentages of cells with subdiploid DNA content and of annexin V-stained cells. Results, Therapy with rHuEpo did not affect CD4+ T cells but decreased the percentage of CD8+ T cells in peripheral blood. The intensity of apoptosis in both CD4+ and CD8+ T cells at baseline was lower in HD patients than in healthy volunteers, and increased in those treated with rHuEpo. In vitro, rHuEpo did not induce apoptosis in PBMCs. The percentage of CD8+Fas+ T cells was constant, while that of CD8+TNFRI+ cells declined during follow-up. There was an increase in the percentage of CD28+ T cells, mainly in the CD8+ compartment, as early as 1 month after the introduction of rHuEpo. CONCLUSIONS: Treatment with rHupo caused a decline of CD8+ T cells in HD patients, which most probably was mediated via the TNFRI-related apoptotic pathway and was independent of Fas expression. Apoptosis in vitro was not directly influenced by rHuEpo, suggesting that the process in vivo was only initiated by rHuEpo supplementation.     

Long-term effects on quality of life in haemodialysis patients of correction of anaemia with erythropoietin

Quality of life assessments were performed in 24 haemodialysispatients (10 males, 14 females, age 45 ±15 years) undergoingrHuEpo treatment. The results in the rHuEpo-treated patientswere compared with those in eight haemodialysis patients noton rHuEpo and with the results of a nationwide study of dialysispatients in Sweden (carried out before rHuEpo was registered).Survey questionnaires (112 items, divided into three dimensions,i.e. physical, social, and emotional wellbeing) were completedbefore treatment (Hb 73± 1.1 g/1), when the target Hbvalue of 10 g/dl was reached (1–7 months) and in 14 patients1 year after correction of the anaemia. Before treatment, therHuEpo group had significantly more complaints about poor appetite,fatigue, and irritability than the controls. After the anaemiawas corrected, the rHuEpo group had significantly improved physicaland emotional wellbeing. The most significant changes occurredin satisfaction with health, physical activities of daily life,and fatigue. Alterations in emotional symptoms, such as depressionand apathy, were less pronounced. Only minor changes were observedin their social wellbeing. One year after correction of theanaemia, the improvements in physical and emotional wellbeingwere still present in the rHuEpo-treated patients. A positiveeffect was also noted on hospitalization rate. Scores for thesubdimensions of satisfaction with health, sexual adjustment,physical symptoms, and emotional wellbeing improved in the rHuEpo-treatedgroup and reached a level that was the same, or even higher,than the scores in the dialysis patients in the nationwide study.In conclusion, the quality of life improved during rHuEpo treatment.The greatest changes were seen in satisfaction with health,physical activity, and emotional wellbeing. The positive effectsobserved after the correction of anaemia persisted after morethan a year on rHuEpo treatment.     

Increased red cell 2,3-diphosphoglycerate levels in haemodialysis patients treated with erythropoietin

The efficacy of recombinant human erythropoietin (rHuEpo) forthe treatment of renal anaemia is well established. To assessthe effect of rHuEpo treatment on physical performance we evaluatedphysical working capacity, oxygen uptake and red cell 2,3diphosphoglycerate(DPG) values at rest and during and after exercise on a bicyclespiroergometer in eight chronically haemodialysed patients.Follow-up examination was carried out after a mean of 14 weeks(range 9–19 weeks), when mean haemoglobin had increasedfrom 7.8 to a stable value of 13.0 g/dl in response to rHuEpotreatment (P<0.001). Physical working capacity and oxygenuptake at the anaerobic threshold (4 rnrnol/l blood lactateconcentration) increased from 68±12 to 80±16 wattsand 0.95±0.14 to 1.10±0.20 l/min, respectively(P<0.01). DPG, which determines oxygen affinity to haemoglobinin red cells, increased by 13% from 13.7±1.5 to 15.5±2.2pmol/g Hb (P<0.05 ). With maximal exercise mean DPG valuessignificantly decreased to a much lower level without rHuEpotreatment than after correction of anaemia. Therefore rHuEpotreatment results both in better oxygen transport capacity andreduced intraerythrocytic oxygen affinity, which is followedby improved oxygen delivery to tissues per unit of haemoglobin.These effects may explain the improvement of exercise capacityobserved in dialysis patients after rHuEpo treatment.     

Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients.

BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22). CONCLUSIONS: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.     

Blood 8-hydroxy-2'-deoxyguanosine is associated with erythropoietin resistance in haemodialysis patients.

BACKGROUND: 8-Hydroxy-2'-deoxyguanosine (8-OHdG), a product of oxidized DNA, is increased in haemodialysis (HD) patients, but the clinical relevance of enhanced 8-OHdG production in these patients remains unknown. METHODS: We cross-sectionally measured serum 8-OHdG in 73 patients on maintenance HD (age 68+/-2 years, time on HD 85+/-11 months, male/female=42/31), and examined the relationship between blood 8-OHdG and the severity of renal anaemia and the weekly dosage of recombinant human erythropoietin (rHuEPO). RESULTS: There was a significant increase in serum 8-OHdG in HD patients compared with normal subjects. Serum 8-OHdG was positively correlated with the patients' age (r=0.231, P<0.05) but not with the duration of HD. Serum 8-OHdG was significantly higher in diabetic subjects than in non-diabetic subjects (P<0.05). Serum 8-OHdG had a significant inverse correlation with haemoglobin (Hb) (r=-0.526, P<0.01) but a positive correlation with the rHuEPO dose (r=0.443, P<0.01) and the ratio of the weekly rHuEPO dose divided by Hb (r=0.487, P<0.01). Serum 8-OHdG was not correlated with inflammatory and nutritional parameters. CONCLUSIONS: These findings suggest that the elevation of circulating 8-OHdG may be associated, at least in part, with rHuEPO resistance in HD patients.     

Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients.

BACKGROUND: Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. METHODS: In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n=12) or 80 mg (n=11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (C(max), t(max), AUC, t(1/2)) compared between single and multiple dosing, and between the different doses. RESULTS: The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite ortho-hydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxy-metabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. CONCLUSION: While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.     

The influence of erythropoietin on cytokines in haemodialysis patients

Summary: In this study, the administration of erythropoietin to haemodialysis patients revealed its immunomodulating properties. to dissociate the immunological effects of erythropoietin action from its haematological effects the patients in our study were administered recombinant human erythropoietin (rhEpo) at the doses that would not affect erythropoiesis. After baseline data had been obtained, six haemodialysis patients were given rhEpo (Eprex-Cilag) at the dose 7-10 U/kg bodyweight/s.c., three times a week, for 12 weeks. All patients maintained a stable haemoglobin concentration; no blood transfusions were required. Serum levels of tumour necrosis factor (TNF), IL-2 and IL-6 levels of the study patients and the four control patients, not receiving rhEpo, were monitored every 2 weeks. the levels of IL-6 and TNF remained unchanged; however, a low serum level of IL-2, recorded before therapy, increased gradually for 10 weeks until it reached the values observed in normal healthy humans (P<0.01). After that it dropped to the initial values. During the study the red blood cell numbers did not change. This study supports the thesis that erythropoietin administered to haemodialysis patients not only corrects anaemia but also independently modulates immunological response.     

Vitamin C plasma level and response to erythropoietin in patients on maintenance haemodialysis.

BACKGROUND: Intravenous vitamin C supplementation to haemodialysis patients might ameliorate responsiveness to recombinant human erythropoietin (rHuEpo). This study was performed to analyse the relation between vitamin C plasma concentration and response to rHuEpo. METHODS: In a cross-sectional, single-centre observational study including all haemodialysis patients, pre-dialysis plasma vitamin C concentrations were measured by high-performance liquid chromatography and response to rHuEpo (haemoglobin concentration/international units rHuEpo/kg/week) was recorded together with baseline laboratory data. RESULTS: Univariate analysis yielded a significant correlation between vitamin C plasma levels and response to rHuEpo (n = 130, r = 0.25, P = 0.004), which still persisted after adjustment for transferrin saturation, C-reactive protein, malondialdehyde, parathyroid hormone, route of rHuEpo administration, residual renal function and diabetes mellitus (adjusted r = 0.23, P = 0.014). Analysis per quartiles of vitamin C plasma level revealed a significantly lower response to rHuEpo with decreasing vitamin C values (P = 0.026). CONCLUSIONS: In unselected haemodialysis patients, vitamin C plasma levels account, at least partially, for the response to rHuEpo. Larger-sized interventional studies are needed to find out whether vitamin C plasma levels may or may not appropriately reflect the potential beneficial effect of vitamin C supplements on rHuEpo responsiveness.     

Switching from subcutaneous to intravenous erythropoietin alpha in haemodialysis patients requires a major dose increase.

BACKGROUND: A change in the licensing arrangements for the use of erythropoietin alpha in haemodialysis patients has required a switch in the route of administration from subcutaneous (SC) to intravenous (IV). Previous work suggested that the IV route was less efficacious but studies since the enforced switch have not confirmed this. METHODS: We studied haemoglobin levels and the mean weekly dose of erythropoietin alpha in 86 haemodialysis patients at monthly intervals over the 6 month period before and after a change in the route of administration of erythropoietin alpha from SC to IV. Changes in other parameters known to be associated with erythropoietin response were also monitored. RESULTS: Mean haemoglobin level fell following the switch from 11.9 g/dl+/-1.4 at baseline to 11.3 g/dl+/-1.4 at 1 month (P = 0.001) and to a trough of 11.0 g/dl+/-1.3 at 2 months (P<0.001) before partial recovery to 11.4 g/dl+/-1.2 (P = 0.007) at 6 months. Mean weekly dose of erythropoietin after 2 months was significantly higher than baseline (8791 IU+/-5314 vs 8035 IU+/-4893). The dose continued to increase and by 6 months was 10605 IU (P<0.001), 32% higher than baseline. There was a small reduction in residual renal function, which was an independent predictor of change in dose requirement. There was a small increase in parathyroid hormone levels, but no change in serum ferritin, dosing frequency, total Kt/V, serum albumin, normalised protein catabolic rate, C-reactive protein, hospitalization rate and dialyser reuse rate. CONCLUSIONS: Switching from SC to IV erythropoietin alpha caused a significant fall in haemoglobin levels in the first 2 months. This was partially reversed by 6 months at the expense of a 32% dose increase in the dose of erythropoietin alpha by 6 months. The economic impact may be considerable.     

Insulin action on glucose and protein metabolism during L-carnitine supplementation in maintenance haemodialysis patients.

BACKGROUND: Impaired protein anabolism and insulin resistance are characteristic features of maintenance haemodialysis patients. We have used a randomised, matched-paired, double-blind, placebo-controlled experimental design to determine the capability of intravenous L-carnitine supplementation to modify insulin resistance and protein catabolism in non-diabetic patients with end-stage renal disease (ESRD) undergoing chronic haemodialysis treatment. METHODS: L-carnitine (20 mg x kg(-1)) (n = 9) or placebo (n = 10) were given intravenously at the end of seven consecutive dialysis sessions. Whole-body protein and glucose metabolism were assessed on interdialytic days by the L[1-(13)C]leucine and the [2,2-(2)H(2)]glucose kinetic models in the postabsorptive state and during euglicemic hyperinsulinemic clamp studies at baseline and at the end of the treatment period. RESULTS: L-carnitine supplementation was associated with lower (P < 0.05) rates of leucine oxidation (-11 +/- 12%) and appearance from proteolysis (-6 +/- 2%) during the clamp studies than after placebo supplementation. The rates of glucose appearance in the postabsorptive state did not change significantly in the patients receiving L-carnitine treatment. Insulin-mediated glucose disappearance was improved by L-carnitine only in those patients (n = 5) (+18 +/- 3%, P < 0.05 vs placebo group, n = 5) with greater baseline insulin resistance, selected according to the median value of insulin sensitivity before treatment. CONCLUSIONS: L-carnitine supplementation was associated with protein-sparing effects in maintenance haemodialysis patients during hyperinsulinemia.     

Intravenous versus subcutaneous administration of recombinant human erythropoietin in patients on haemodialysis and CAPD.

The most effective route of administration of rHuEpo is still a matter of discussion. Prospectively we studied subcutaneous (s.c.) versus intravenous (i.v.) administration in three comparable groups of patients; HD-s.c. (n = 9), HD-i.v. (n = 11), and CAPD-s.c. (n = 9). All the groups initially received 50 units/kg three times weekly. During the first 8 weeks dose adjustments were made only if target haemoglobin exceeded 11.3 g/dl (7 mM). Target haemoglobin was reached after 84 (42-98) days in the i.v. group and 42 (14-77) and 42 (28-56) respectively in the HD-s.c. and CAPD groups. The difference was statistically significant (P less than 0.05). Even the cumulative doses to reach target haemoglobin were significantly less in the two s.c. groups. To maintain haemoglobin at about 11.3 g/dl, weekly doses were as follows: HD-i.v. 125 U/kg (86-168), HD-s.c. 63 U/kg (20-85), and CAPD 72 U/kg (31-100). The total observation time after the target haemoglobin level was reached, was median 130 (114-264) days. The difference between the i.v. group and the two s.c. groups was statistically significant, (P less than 0.05) whereas there was no difference between the s.c. groups. We conclude that s.c. administration of rHuEpo is more effective in induction as well as in maintenance therapy and that s.c. administration is equally efficient in HD and CAPD patients.